6-phenyl-1h,4h-{8 1,2,4{9 oxadiazalo{8 4,3-2{9 {8 1,4{9 benzodiazepin-1-ones

ABSTRACT

R is hydrogen or chlorine and is prepared by reacting 7-chloro2-(hydroxyamino)-5-phenyl-3H-1,4-benzodiazepine with phosgene in the presence of a base. The invention further comprises the pharmacologically acceptable acid addition salts of compounds of formula II. These compounds and acid addition salts thereof are useful tranquilizers for mammals. 6-Phenyl-1H,4H-(1,2,4)oxadiazolo(4,3-a)benzodiazepin-1-ones of the formula II:

United States Patent [191 Hester, Jr.

[451 Dec. 31, 1974 [54] TRANQiUILI ZER 6-PHENYL-1H,4H

[1 ,2 ,4] OXADIAZALO[4,3-a] [l ,4] BENZODIAZEPIN-l-ONES [75] Inventor:Jackson B. Hester, Jr., Galesburg,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: May 2, 1973 21 Appl. No.: 356,372

Related U.S. Application Data [63] Continuation-in-part of Ser. No.178,792, Sept. 8,

1971, abandoned.

[52] U.S. Cl. 260/307 A, 260/239 BD, 424/272 [51] Int. Cl C07d 85/52[58] Field of Search 260/307 A [56] References Cited OTHER PUBLICATIONSHester et al.-Tetrahedron Letters 20, 1971 Behr Fiveand Six-MemberedCompounds With Nitrogen And Oxygen (1962)Intersc. Publ. p. 256.

Primary Examiner-Raymond V. Rush Attorney, Agent, or FirmHans L. Berneis[5 7] ABSTRACT R is hydrogen or chlorine and is prepared by reacting7-chloro-2-(hydroxyamino)-5-phenyl-3H-l ,4- benzodiazepine with phosgenein the presence of a base.

The invention further comprises the pharmacologically acceptable acidaddition salts of compounds of formula II.

These compounds and acid addition salts thereof are useful tranquilizersfor mammals.

5 Claims, No Drawings 1 TRANQUILIZER 6-PHENYL-lH,4H-[l,2,4] OXADIAZALO[4,3-2] [1 ,4]BENZODIAZEPIN-1- ONES CROSS REFERENCE TO RELATEDAPPLICATION This application is a continuation-in-part of applicationSer. No. 178,792 filed Sept. 8, 1971, and now abandoned.

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention isdirected to new organic compounds and is particularly concerned withnovel 8-chloro-6- phenyll H,4H-[ 1 ,2,4]oxadiazolo[4,3- a] 1,4]benzodiazepin-l-one s and a process for the production thereof.

The novel compound and the process of production therefor can beillustratively represented as follows:

wherein R is hydrogen or chlorine.

The invention comprises also the pharmacologically acceptable acidaddition salts of II.

The process of this invention comprises treating an8-chloro-2-hydroxyaminobenzodiazepine I with phosgene in the presence ofa base to obtain the oxadiazole compound II.

2. Description of the Preferred Embodiment The acid addition salts ofcompounds of formula II contemplated in this invention, are thehydrochlorides, hydrobromides, hydriodides, sulfates, phosphates,cyclohexanesulfamates, methanesulfonates and the like, prepared byreacting a compound of formula II with an excess of the selectedpharmacologically acceptable acid.

Sedative effects of 8-chloro-6-phenyl-lH,4I-I-[1,2,4]-oxadiazolo[4,3-a][ 1 ,4]benzodiazepin-l-one shown by the following testsin mice:

Chimney test: [Med. Exp. 4, 145 (1961)]: The effective intraperitonealdosage for 50% of the mice (ED is 79 mg./kg. The test determines theability of mice to back up and out of a vertical glass cylinder within30 seconds. At the effective dosage, 50% of the mice failed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization. ED equals the dose of the test compound at which 50% ofthe mice remain in the dish. The ED (intraperitoneal administration) inthis test is 7.1 mg./kg.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than 1 minute. TheED (intraperitoneal administration) is 7.1 mg./kg.

Nicotine antagonism test: Mice in a group of 6 are injected with thetest compound (8-chloro-6-phenyl- 1H, 4H-[l,2,4]oxadiazolo[4,3-a][1,4]benzodiazepin-l-one. Thirty minutes later the mice includingcontrol (untreated) mice are injected with nicotine salicylate (2mg./kg.). The

' control mice show overstimulation, i.e., (1) running convulsionsfollowed by (2) tonic extensor fits followed by (3) death. Anintraperitoneal dosage of 23 mg./kg. of the test compound protected 50%of the mice against (2) and 20 mg./kg. against (3) 50- Antagonism tostrychnine (as sulfate): The effective dosage (EDso) of8-chloro-6-phenyl-1I-I,4H-[1,2,4]-oxadiazolo[4,3-a][1,4]benzodiazepinel-one is 178 mg./kg. orallyin mice. The test consists in orally administering into groups of 6 micethe test compound and 30 minutes later 3 mg./kg. strychnine sulfateintraperitoneally. The survivors after 4 hours reflect the activity ofthe compound as a muscle relaxant and antispasmodic. A dosage of 3mgjkg. of strychnine sulfate is routinely fatal to all the control mice.

The pharmaceutical forms contemplated by this invention includepharmaceutical compositions suited for oral, parenteral andrectal use,e.g., tablets, powder packets, cachets, dragees, capsules, solutions,suspensions, sterile injectable forms, suppositories, bougies, and thelike. Suitable diluents or carriers such as carbohydrates, lactose,proteins, lipids, calcium phosphate, cornstrach, stearic acid,methylcellulose and the like may be used as carriers or for coatingpurposes. Water or oil, e.g., sesame oil, safflower oil, cottonseed oil,peanut oil may be used for preparing solutions or suspensions of theactive drug. Sweetening, coloring, and flavoring agents may be added.

For mammals and birds, food premixes, with starch, oatmeal, driedfishmeat, fishmeal, flour, and the like can be prepared.

As tranquilizers, the compoundsof formula II can be used in dosage of l-75 mg./kg. in oral or injectable preparations as described above,preferably from 5 to mg./kg. to alleviate tension and anxiety inmammals, or birds, such as e.g., occurs when animals are in travel.

The starting products of this invention (formula 1); are produced asshown in the preparations.

In carrying out the process of this invention a 2- hydroxyamino-5-phenyl-3H-l,4-benzodiazepine (l) is allowed to react withphosgene in the presence of a base. In the preferred embodiment of thisreaction, the base is an organic base e.g. triethylamine,tripropylamine, diethylbutylamine, pyridine, N-methylpiperidine or thelike, dissolved in an organic solvent inert in this reaction, e.g.toluene, tetrahydrofuran, dioxane, diethylether, benzene or the like.The temperature is preferably kept low between C. while phosgene gas isbubbled into the mixture for 10-60 minutes. After the phosgene additionis terminated the reaction mixture is kept between 0-50 C. for 0.5 to 2hours.

The resulting 6-phenyl-1H,4H-[1,2,4]oxadiazolo[4,3-a]-[1,4]benzodiazepin-l-one is recovered andpurified by standard procedures, such as removal of solvents and excessreactants, extraction, chromatography, and crystallization.

The following Preparation and Example is illustrative of the process andproducts of the present invention, but are not to be construed aslimiting.

PREPARATION l Z-(Hydroxyamino)-7-chloro-5-phenyl-3H-1,4- benzodiazepineA mixture of 14.4 g. (0.05 mole) of 7-chloro-1,3-dihydro-S-phenyl-ZH-1,4-benzodiazepine-2-thione, hydroxylaminehydrochloride (4.55 g.), sodium bicarbonate (5.45 g.) and methanol (250ml.) is refluxed for 1.5 hours with a stream of nitrogen bubblingthrough the mixture. The cooled mixture is filtered and the filtrate isconcentrated in vacuo to give a residue. This residue is chromatographedon silica gel (750 g.); 150-m1. fractions are collected. The product iseluted with 2% triethylamine-13%.methanol-85% ethyl acetate andcrystallized from ethyl acetate to give 4.92 g. of 2-(hydroxyamino)-7-chloro-5-phenyl-3H-1,4- benzodiazepine of melting point122.5130 C. and 3.38 g. of melting point 128-132 C. The analyticalsample has a melting point of l26-130 C.

Anal. calcd. for C H ClN O:

C, 63.05; H, 4.23; CI, 12.41; N, 14.71. Found:

C, 63.13; H, 4.40; Cl, 12.31; N, 14.52.

PREPARATION 2 2-(Hydroxyamino)-7-chloro-5-(o-chlorophenyl)-3H- l,4-benzodiazepine EXAMPLE 18-Chloro-6-phenyl-1H,4H-[1,2,4]oxadiazolo[4,3-a]- 1,4]benzodiazepin-l-one A stirred solution of 7-chloro-2-(hydroxyamino)-5-phenyl-3H-1,4-benzodiazepine (2.86 g., 0.0100 mole) and triethylamine(3.05 ml., 0.0220 mole) in dry toluene is cooled in an ice bath undernitrogen. Phosgene (0.795 ml., 0.011 mole) is evaporated into thismixture during minutes. Excess phosgene is removed by bubbling a slowstream of nitrogen through the mixture which is removed from the icebath and allowed to EXAMPLE 2 8-chloro-6-(o-chlorophenyl)-1H,4H-[1,2,4]oxadiazolo[4,3-a][1,4]benzodiazepin-1-one In the manner given inExample 1, Z-hydroxyamino- 7-chloro-5-(o-chlorophenyl)-3H-l,4-benzodiazepine is reacted at low temperature with phosgene in thepresence of triethylamine to give8-chloro-6-(ochlorophenyl)-1H,4H-[1,2,4]oxadiazolo[4,3-

a][1,4]benzodiazepin-l-one.

Treating the compound of formula II with a pharmacologically acceptableacid such as hydrochloric, hydrobromic, phosphoric, sulfuric,acetic,propionic, toluene-sulfonic, methanesulfonic, tartaric, citric,lactic, malic, maleic, cyclohexanesulfamic acids produces thepharmacologically acceptable salts of the compound of formula II whichcan be used like the free base compound of formula 11. Salt formation isachieved in conventional manner by reacting the compound of formula IIwith excess of a selected acid in a suitable medium e.g. water, a loweralkanol, ether, or acetone and recovering the salt by evaporating thesolvent, preferably in vacuo.

I claim:

1. A compound selected from the group consisting of a 6-phenyl-1H,4H-[l',2,4]oxadiazolo[4,3- a][1,4]benzodiazepin-1-one of the formula 11wherein R is hydrogen or chlorine and the pharmacologically acceptableacid addition salts thereof.

2. A compound according to claim 1 wherein R is hydrogen and thecompound is therefore 8-chloro-6- phenyl-1H,4H-[1,2,4]oxadiazolo[4,3-

a] 1 ,4]benzodiazepin-1-one.

3. A compound according to claim 1 wherein R is chloro and the compoundis therefore 8-chloro-6-(ochlorophenyl)-lH,4H-[1,2,4]oxadiazolo[4,3-

a][ 1 ,41benzodiazepin- 1 -one.

4. A process for the production of a 6-phenyl-ll-L4H- the formula I[1,2,4]oxadiazolo[4,3-a][1,4]benzodiazepin-l-one of the formula IIwherein R is defined as above, in an organic solvent,

inert in the reaction with phosgene, in the presence of an organic baseto obtain the corresponding6-phenyllH,4H-[l,2,4]-oxadiazolo-[4,3-a][1,4]benzodiazepinl-one ofabove.

wherein R is hydrogen or chlorine, which comprises the 5. The process ofclaim 1 wherein the solvent is tolustep: treating at 0 to 10C. asolution of 7-chlor0-2- ene.

(hydroxyamino)-5-phenyl-3H-1,4-benzodiazepine of

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A 6PHENYL-1H,4H-(1,2,5)OXADIAZOLO(4,3-A)(1,4)BENZODIAZEPIN1-ONE OF THE FORMULA II 2.A compound according to claim 1 wherein R is hydrogen and the compoundis therefore 8-chloro-6-phenyl-1H,4H-(1,2,4)oxadiazolo(4,3-a)(1,4)benzodiazepin-1-one.
 3. A compound according toclaim 1 wherein R is chloro and the compound is therefore8-chloro-6-(o-chlorophenyl)-1H,4H-(1,2,4)oxadiazolo(4,3-a)(1,4)benzodiazepin-1-one.
 4. A process for theproduction of a 6-phenyl-1H,4H-(1,2,4)oxadiazolo(4,3-a)(1,4)benzodiazepin-1-one of the formula II
 5. Theprocess of claim 1 wherein the solvent is toluene.